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J. Biol. Chem., Vol. 280, Issue 34, 30481-30489, August 26, 2005

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Extracellular Matrix Proteoglycans Control the Fate of Bone Marrow Stromal Cells^*

Yanming Bi, Christina H. Stuelten, Tina Kilts, Sunil Wadhwa, Renato V. Iozzo¶, Pamela G. Robey, Xiao-Dong Chen||, and Marian F. Young**

From the Craniofacial and Skeletal Diseases Branch, NIDCR and the Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892 and the ^¶Departments of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Extracellular matrix glycoproteins and proteoglycans bind a variety of growth factors and cytokines thereby regulating matrix assembly as well as bone formation. However, little is known about the mechanisms by which extracellular matrix molecules modulate osteogenic stem cells and bone formation. Using mice deficient in two members of the small leucine-rich proteoglycans, biglycan and decorin, we uncovered a role for these two extracellular matrix proteoglycans in modulating bone formation from bone marrow stromal cells. Our studies showed that the absence of the critical transforming growth factor- (TGF-)-binding proteoglycans, biglycan and decorin, prevents TGF- from proper sequestration within the extracellular matrix. The excess TGF- directly binds to its receptors on bone marrow stromal cells and overactivates its signaling transduction pathway. Overall, the predominant effect of the increased TGF- signaling in bgn/dcn-deficient bone marrow stromal cells is a "switch in fate" from growth to apoptosis, leading to decreased numbers of osteoprogenitor cells and subsequently reduced bone formation. Thus, biglycan and decorin appear to be essential for maintaining an appropriate number of mature osteoblasts by modulating the proliferation and survival of bone marrow stromal cells. These findings underscore the importance of the micro-environment in controlling the fate of adult stem cells and reveal a novel cellular and molecular basis for the physiological and pathological control of bone mass.

Received for publication, January 18, 2005 , and in revised form, May 5, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence may be addressed: University of Arkansas, College of Medicine, 4301 West Markam Str., Slot 587, Little Rock, AR 72205-7199. Tel.: 501-868-1503; Fax: 501-686-8148; E-mail: xdchen{at}uams.edu.

^** To whom correspondence may be addressed: Bldg. 30, Rm. 225, NIDCR, National Institutes of Health, 9000 Rockville Pike, MSC 4320, Bethesda, MD 20892. Tel.: 301-496-8860; Fax: 301-402-0824; E-mail: myoung{at}dir.nidcr.nih.gov.

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